Schizophrenia and cocaine dependence produce disability, in part, by impairing executive cognitive function. Also, schizophrenic patients are at increased risk for developing cocaine dependence. When abstinent from cocaine, comorbid patients show reduced symptoms, but poorer executive cognitive function than other schizophrenic patients. This proposal probes the interactive cognitive neuroscience of schizophrenia and cocaine dependence. It builds on the work of our late colleague, Patricia Goldman-Rakic, who showed in monkeys that prefrontal cortex (PFC) activity during the maintenance phase of working memory (WM) was dependent upon dopamine D1 receptor function, while PFC activity during the response selection phase of WM was dependent upon D2 receptor function. We propose to use functional magnetic resonance imaging (fMRI) to compare PFC activity associated with WM and cortical functional connectivity in four groups of subjects: healthy individuals, abstinent cocaine dependent individuals, schizophrenia patients, and abstinent cocaine dependent schizophrenic patients. Our pilot data suggest that the comorbid group shows greater PFC activity deficits in the maintenance phase of WM than either single diagnosis group, perhaps related to greater deficits in PFC D1 receptor function. However, the comorbid group shows greater response phase activity than either single diagnosis group or healthy subjects, suggestive of a cocaine use-related enhancement of PFC D2 receptor function. By highlighting novel circuit adaptations that contribute to cognitive dysfunction associated with the interplay of schizophrenia and cocaine dependence, this application may shed new light on PFC mechanisms that contribute to poorer cognitive outcomes associated with schizophrenia, cocaine dependence, and their comorbidity. PUBLIC HEALTH RELEVANCE This project may help us to understand how schizophrenia and cocaine abuse affect prefrontal function how these factors interact in those who are co-morbid for schizophrenia and cocaine dependence. Such knowledge may help us to develop better treatments for those who are comorbid for schizophrenia and cocaine dependence. [unreadable] [unreadable] [unreadable]